Transformation of motion pattern selectivity from retina to superior colliculus.

The superior colliculus (SC) is a prominent and conserved visual center in all vertebrates. In mice, the most superficial lamina of the SC is enriched with neurons that are selective for the moving direction of visual stimuli. Here we study how these direction selective neurons respond to complex motion patterns known as plaids, using two-photon calcium imaging in awake male and female mice. The plaid pattern consists of two superimposed sinusoidal gratings moving in different directions, giving an apparent pattern direction that lies between the directions of the two component gratings. Most direction selective neurons in the mouse SC respond robustly to the plaids and show a high selectivity for the moving direction of the plaid pattern but not of its components. Pattern motion selectivity is seen in both excitatory and inhibitory SC neurons and is especially prevalent in response to plaids with large cross angles between the two component gratings. However, retinal inputs to the SC are ambiguous in their selectivity to pattern versus component motion. Modeling suggests that pattern motion selectivity in the SC can arise from a nonlinear transformation of converging retinal inputs. In contrast, the prevalence of pattern motion selective neurons is not seen in the primary visual cortex (V1). These results demonstrate an interesting difference between the SC and V1 in motion processing and reveal the SC as an important site for encoding pattern motion.Significance Statement An important function of the visual system is to encode the direction of complex motion patterns in the environment. Studies using the plaid stimulus have revealed neurons in different cortical areas that are tuned to either pattern motion or component motion, but how neurons in the SC respond to plaids has not been studied. Here we show that direction selective neurons in the mouse SC respond to plaids with a clear pattern motion selectivity, at a level not seen in the retina or V1. Our results thus provide new information regarding the function and organization of the early visual system and highlight the importance of SC circuits in computing complex motion.

Visible-Light Optical Coherence Tomography Fibergraphy of the Tree Shrew Retinal Ganglion Cell Axon Bundles.

We seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.

Comparative In Vivo Imaging of Retinal Structures in Tree Shrews, Humans, and Mice.

Rodent models, such as mice and rats, are commonly used to examine retinal ganglion cell damage in eye diseases. However, as nocturnal animals, rodent retinal structures differ from primates, imposing significant limitations in studying retinal pathology. Tree shrews (Tupaia belangeri) are small, diurnal paraprimates that exhibit superior visual acuity and color vision compared with mice. Like humans, tree shrews have a dense retinal nerve fiber layer (RNFL) and a thick ganglion cell layer (GCL), making them a valuable model for investigating optic neuropathies. In this study, we applied high-resolution visible-light optical coherence tomography to characterize the tree shrew retinal structure in vivo and compare it with that of humans and mice. We quantitatively characterize the tree shrew's retinal layer structure in vivo, specifically examining the sublayer structures within the inner plexiform layer (IPL) for the first time. Next, we conducted a comparative analysis of retinal layer structures among tree shrews, mice, and humans. We then validated our in vivo findings in the tree shrew inner retina using ex vivo confocal microscopy. The in vivo and ex vivo analyses of the shrew retina build the foundation for future work to accurately track and quantify the retinal structural changes in the IPL, GCL, and RNFL during the development and progression of human optic diseases.

Maternal diet during early gestation influences postnatal taste activity-dependent pruning by microglia.

A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in controls involved the complement system and is likely driven by NaCl-elicited taste activity. In contrast, offspring of mothers with an early dietary manipulation failed to prune gustatory terminal fields even though peripheral taste activity developed normally. The ability to prune in these mice was rescued by activating myeloid cells postnatally, and conversely, pruning was arrested in controls with the loss of myeloid cell function. The altered pruning and myeloid cell function appear to be programmed before the peripheral gustatory system is assembled and corresponds to the embryonic period when microglia progenitors derived from the yolk sac migrate to and colonize the brain.

Widespread and Multifaceted Binocular Integration in the Mouse Primary Visual Cortex.

The brain combines two-dimensional images received from the two eyes to form a percept of three-dimensional surroundings. This process of binocular integration in the primary visual cortex (V1) serves as a useful model for studying how neural circuits generate emergent properties from multiple input signals. Here, we perform a thorough characterization of binocular integration using electrophysiological recordings in the V1 of awake adult male and female mice by systematically varying the orientation and phase disparity of monocular and binocular stimuli. We reveal widespread binocular integration in mouse V1 and demonstrate that the three commonly studied binocular properties-ocular dominance, interocular matching, and disparity selectivity-are independent of each other. For individual neurons, the responses to monocular stimulation can predict the average amplitude of binocular response but not its selectivity. Finally, the extensive and independent binocular integration of monocular inputs is seen across cortical layers in both regular-spiking and fast-spiking neurons, regardless of stimulus design. Our data indicate that the current model of simple feedforward convergence is inadequate to account for binocular integration in mouse V1, thus suggesting an indispensable role played by intracortical circuits in binocular computation.SIGNIFICANCE STATEMENT Binocular integration is an important step of visual processing that takes place in the visual cortex. Studying the process by which V1 neurons become selective for certain binocular disparities is informative about how neural circuits integrate multiple information streams at a more general level. Here, we systematically characterize binocular integration in mice. Our data demonstrate more widespread and complex binocular integration in mouse V1 than previously reported. Binocular responses cannot be explained by a simple convergence of monocular responses, contrary to the prevailing model of binocular integration. These findings thus indicate that intracortical circuits must be involved in the exquisite computation of binocular disparity, which would endow brain circuits with the plasticity needed for binocular development and processing.

Visible-Light Optical Coherence Tomography Fibergraphy of the Tree Shrew Retinal Ganglion Cell Axon Bundles.

We seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.

Mapping visual functions onto molecular cell types in the mouse superior colliculus.

The superficial superior colliculus (sSC) carries out diverse roles in visual processing and behaviors, but how these functions are delegated among collicular neurons remains unclear. Here, using single-cell transcriptomics, we identified 28 neuron subtypes and subtype-enriched marker genes from tens of thousands of adult mouse sSC neurons. We then asked whether the sSC's molecular subtypes are tuned to different visual stimuli. Specifically, we imaged calcium dynamics in single sSC neurons in vivo during visual stimulation and then mapped marker gene transcripts onto the same neurons ex vivo. Our results identify a molecular subtype of inhibitory neuron accounting for ∼50% of the sSC's direction-selective cells, suggesting a genetic logic for the functional organization of the sSC. In addition, our studies provide a comprehensive molecular atlas of sSC neuron subtypes and a multimodal mapping method that will facilitate investigation of their respective functions, connectivity, and development.

Neural circuits for binocular vision: Ocular dominance, interocular matching, and disparity selectivity.

The brain creates a single visual percept of the world with inputs from two eyes. This means that downstream structures must integrate information from the two eyes coherently. Not only does the brain meet this challenge effortlessly, it also uses small differences between the two eyes' inputs, i.e., binocular disparity, to construct depth information in a perceptual process called stereopsis. Recent studies have advanced our understanding of the neural circuits underlying stereoscopic vision and its development. Here, we review these advances in the context of three binocular properties that have been most commonly studied for visual cortical neurons: ocular dominance of response magnitude, interocular matching of orientation preference, and response selectivity for binocular disparity. By focusing mostly on mouse studies, as well as recent studies using ferrets and tree shrews, we highlight unresolved controversies and significant knowledge gaps regarding the neural circuits underlying binocular vision. We note that in most ocular dominance studies, only monocular stimulations are used, which could lead to a mischaracterization of binocularity. On the other hand, much remains unknown regarding the circuit basis of interocular matching and disparity selectivity and its development. We conclude by outlining opportunities for future studies on the neural circuits and functional development of binocular integration in the early visual system.

Rapid development of motion-streak coding in the mouse visual cortex.

Despite its importance, the development of higher visual areas (HVAs) at the cellular resolution remains largely unknown. Here, we conducted 2-photon calcium imaging of mouse HVAs lateromedial (LM) and anterolateral (AL) and V1 to observe developmental changes in visual response properties. HVA neurons showed selectivity for orientations and directions similar to V1 neurons at eye opening, which became sharper in the following weeks. Neurons in all areas over all developmental stages tended to respond selectively to dots moving along an axis perpendicular to their preferred orientation at slow speeds, suggesting a certain level of conventional motion coding already at eye opening. In contrast, at high speeds, many neurons responded to dots moving along the axis parallel to the preferred orientation in older animals but rarely after eye opening, indicating a lack of motion-streak coding in the earlier stage. Together, our results uncover the development of visual properties in HVAs.

Strong tuning for stereoscopic depth indicates orientation-specific recurrent circuitry in tree shrew V1.

Neurons in the primary visual cortex (V1) are tuned to specific disparities between the two retinal images, which form the neural substrate for stereoscopic vision. We show that V1 neurons in tree shrews, but not in mice, display highly selective responses to narrow ranges of disparity in random-dot stereograms. Surprisingly, V1 neurons in both species show similarly strong tuning to gratings of varying interocular phase differences. This stimulus-dependent dissociation of disparity tuning can be explained by a network model that combines both feedforward and recurrent connections. The features of the model connections are supported by cortical organizations specific to each species. We validate this model by identifying putative inhibitory neurons and confirming their predicted disparity tuning in both species. Together, our studies establish a foundation for using tree shrews in studying binocular vision and raise an exciting possibility of how cortical columns could be uniquely important in computing stereoscopic depth.

Tree Shrews as an Animal Model for Studying Perceptual Decision-Making Reveal a Critical Role of Stimulus-Independent Processes in Guiding Behavior.

Decision-making is an essential cognitive process by which we interact with the external world. However, attempts to understand the neural mechanisms of decision-making are limited by the current available animal models and the technologies that can be applied to them. Here, we build on the renewed interest in using tree shrews (Tupaia belangeri) in vision research and provide strong support for them as a model for studying visual perceptual decision-making. Tree shrews learned very quickly to perform a two-alternative forced choice contrast discrimination task, and they exhibited differences in response time distributions depending on the reward and punishment structure of the task. Specifically, they made occasional fast guesses when incorrect responses are punished by a constant increase in the interval between trials. This behavior was suppressed when faster incorrect responses were discouraged by longer intertrial intervals. By fitting the behavioral data with two variants of racing diffusion decision models, we found that the between-trial delay affected decision-making by modulating the drift rate of a time accumulator. Our results thus provide support for the existence of an internal process that is independent of the evidence accumulation in decision-making and lay a foundation for future mechanistic studies of perceptual decision-making using tree shrews.

Coarse-to-fine processing drives the efficient coding of natural scenes in mouse visual cortex.

The visual system processes sensory inputs sequentially, perceiving coarse information before fine details. Here we study the neural basis of coarse-to-fine processing and its computational benefits in natural vision. We find that primary visual cortical neurons in awake mice respond to natural scenes in a coarse-to-fine manner, primarily driven by individual neurons rapidly shifting their spatial frequency preference from low to high over a brief response period. This shift transforms the population response in a way that counteracts the statistical regularities of natural scenes, thereby reducing redundancy and generating a more efficient neural representation. The increase in representational efficiency does not occur in either dark-reared or anesthetized mice, which show significantly attenuated coarse-to-fine spatial processing. Collectively, these results illustrate that coarse-to-fine processing is state dependent, develops postnatally via visual experience, and provides a computational advantage by generating more efficient representations of the complex spatial statistics of ethologically relevant natural scenes.

Closing the Critical Period Is Required for the Maturation of Binocular Integration in Mouse Primary Visual Cortex.

Binocular matching of orientation preference between the two eyes is a common form of binocular integration that is regarded as the basis for stereopsis. How critical period plasticity enables binocular matching under the guidance of normal visual experience has not been fully demonstrated. To investigate how critical period closure affects the binocular matching, a critical period prolonged mouse model was constructed through the administration of bumetanide, an NKCC1 transporter antagonist. Using acute in vivo extracellular recording and molecular assay, we revealed that binocular matching was transiently disrupted due to heightened plasticity after the normal critical period, together with an increase in the density of spines and synapses, and the upregulation of GluA1 expression. Diazepam (DZ)/[(R, S)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP)] could reclose the extended critical period, and rescue the deficits in binocular matching. Furthermore, the extended critical period, alone, with normal visual experience is sufficient for the completion of binocular matching in amblyopic mice. Similarly, prolonging the critical period into adulthood by knocking out Nogo-66 receptor can prevent the normal maturation of binocular matching and depth perception. These results suggest that maintaining an optimal plasticity level during adolescence is most beneficial for the systemic maturation. Extending the critical period provides new clues for the maturation of binocular vision and may have critical implications for the treatment of amblyopia.

Unraveling circuits of visual perception and cognition through the superior colliculus.

The superior colliculus is a conserved sensorimotor structure that integrates visual and other sensory information to drive reflexive behaviors. Although the evidence for this is strong and compelling, a number of experiments reveal a role for the superior colliculus in behaviors usually associated with the cerebral cortex, such as attention and decision-making. Indeed, in addition to collicular outputs targeting brainstem regions controlling movements, the superior colliculus also has ascending projections linking it to forebrain structures including the basal ganglia and amygdala, highlighting the fact that the superior colliculus, with its vast inputs and outputs, can influence processing throughout the neuraxis. Today, modern molecular and genetic methods combined with sophisticated behavioral assessments have the potential to make significant breakthroughs in our understanding of the evolution and conservation of neuronal cell types and circuits in the superior colliculus that give rise to simple and complex behaviors.

Motion Streak Neurons in the Mouse Visual Cortex.

Motion streaks are smeared representation of fast-moving objects due to temporal integration. Here, we test for motion streak signals in mice with two-photon calcium imaging. For small dots moving at low speeds, neurons in primary visual cortex (V1) encode the component motion, with preferred direction along the axis perpendicular to their preferred orientation. At high speeds, V1 neurons prefer the direction along the axis parallel to their preferred orientation, as expected for encoding motion streaks. Whereas some V1 neurons (∼20%) display a switch of preferred motion axis with increasing speed, others (>40%) respond specifically to high speeds at the parallel axis. Motion streak neurons are also seen in higher visual lateromedial (LM), anterolateral (AL), and rostrolateral (RL) areas, but with higher transition speeds, and many still prefer the perpendicular axis even with fast motion. Our results thus indicate that diverse motion encoding exists in mouse visual cortex, with intriguing differences among visual areas.

Lack of Evidence for Stereotypical Direction Columns in the Mouse Superior Colliculus.

Neurons in the visual system can be spatially organized according to their response properties such as receptive field location and feature selectivity. For example, the visual cortex of many mammalian species contains orientation and direction columns where neurons with similar preferences are clustered. Here, we examine whether such a columnar structure exists in the mouse superior colliculus (SC), a prominent visual center for motion processing. By performing large-scale physiological recording and two-photon calcium imaging in adult male and female mice, we show that direction-selective neurons in the mouse SC are not organized into stereotypical columns as a function of their preferred directions, although clusters of similarly tuned neurons are seen in a minority of mice. Nearby neurons can prefer similar or opposite directions in a largely position-independent manner. This finding holds true regardless of animal state (anesthetized vs awake, running vs stationary), SC depth (most superficial lamina vs deeper in the SC), research technique (calcium imaging vs electrophysiology), and stimulus type (drifting gratings vs moving dots, full field vs small patch). Together, these results challenge recent reports of region-specific organizations in the mouse SC and reveal how motion direction is represented in this important visual center.

Two Is Greater Than One: Binocular Visual Experience Drives Cortical Orientation Map Alignment.

One hallmark of the mature visual cortex is binocularly matched orientation maps. In this issue of Neuron, Chang et al. (2020) show that three different maps exist at vision onset and that binocular visual experience aligns them into a single unified representation.

Development and binocular matching of orientation selectivity in visual cortex: a computational model.

In mouse visual cortex, right after eye opening binocular cells have different preferred orientations for input from the two eyes. With normal visual experience during a critical period, these preferred orientations evolve and eventually become well matched. To gain insight into the matching process, we developed a computational model of a cortical cell receiving orientation selective inputs via plastic synapses. The model captures the experimentally observed matching of the preferred orientations, the dependence of matching on ocular dominance of the cell, and the relationship between the degree of matching and the resulting monocular orientation selectivity. Moreover, our model puts forward testable predictions: 1) The matching speed increases with initial ocular dominance. 2) While the matching improves more slowly for cells that are more orientation selective, the selectivity increases faster for better matched cells during the matching process. This suggests that matching drives orientation selectivity but not vice versa. 3) There are two main routes to matching: the preferred orientations either drift toward each other or one of the orientations switches suddenly. The latter occurs for cells with large initial mismatch and can render the cells monocular. We expect that these results provide insight more generally into the development of neuronal systems that integrate inputs from multiple sources, including different sensory modalities.NEW & NOTEWORTHY Animals gather information through multiple modalities (vision, audition, touch, etc.). These information streams have to be merged coherently to provide a meaningful representation of the world. Thus, for neurons in visual cortex V1, the orientation selectivities for inputs from the two eyes have to match to enable binocular vision. We analyze the postnatal process underlying this matching using computational modeling. It captures recent experimental results and reveals interdependence between matching, ocular dominance, and orientation selectivity.

Effects of Locomotion on Visual Responses in the Mouse Superior Colliculus.

Visual responses are extensively shaped by internal factors. This effect is drastic in the primary visual cortex (V1), where locomotion profoundly increases visually-evoked responses. Here we investigate whether a similar effect exists in another major visual structure, the superior colliculus (SC). By performing two-photon calcium imaging of head-fixed male and female mice running on a treadmill, we find that only a minority of neurons in the most superficial lamina of the SC display significant changes during locomotion. This modulation includes both increase and decrease in response amplitude and is similar between excitatory and inhibitory neurons. The overall change in the SC is small, whereas V1 responses almost double during locomotion. Additionally, SC neurons display lower response variability and less spontaneous activity than V1 neurons. Together, these experiments indicate that locomotion-dependent modulation is not a widespread phenomenon in the early visual system and that the SC and V1 use different strategies to encode visual information.SIGNIFICANCE STATEMENT Visual information captured by the retina is processed in parallel through two major pathways, one reaching the primary visual cortex through the thalamus, and the other projecting to the superior colliculus. The two pathways then merge in the higher areas of the visual cortex. Recent studies have shown that behavioral state such as locomotion is an essential component of vision and can strongly affect visual responses in the thalamocortical pathway. Here we demonstrate that neurons in the mouse superior colliculus and primary visual cortex display striking differences in their modulation by locomotion, as well as in response variability and spontaneous activity. Our results reveal an important "division of labor" in visual processing between these two evolutionarily distinct structures.

Transformation of Feature Selectivity From Membrane Potential to Spikes in the Mouse Superior Colliculus.

Neurons in the visual system display varying degrees of selectivity for stimulus features such as orientation and direction. Such feature selectivity is generated and processed by intricate circuit and synaptic mechanisms. A key factor in this process is the input-output transformation from membrane potential (Vm) to spikes in individual neurons. Here, we use in vivo whole-cell recording to study Vm-to-spike transformation of visual feature selectivity in the superficial neurons of the mouse superior colliculus (SC). As expected from the spike threshold effect, direction and orientation selectivity increase from Vm to spike responses. The degree of this increase is highly variable, and interestingly, it is correlated with the receptive field size of the recorded neurons. We find that the relationships between Vm and spike rate and between Vm dynamics and spike initiation are also correlated with receptive field size, which likely contribute to the observed input-output transformation of feature selectivity. Together, our findings provide useful information for understanding information processing and visual transformation in the mouse SC.